title: Population-specific GSTM1 copy number variation.
abstract: As one of the major glutathione conjugation enzymes, GSTM1 detoxifies a number of drugs and xenobiotics. Its expression and activity have been shown to correlate both with cancer risks and drug resistance. Through a genome-wide association study, we identified a significant association between HapMap SNP rs366631 and GSTM1 expression. In this study, utilizing lymphoblastoid cell lines derived from International HapMap Consortium CEU and YRI populations, we designed and performed site-specific genotyping assays for both rs366631 and a highly homologous GSTM1 upstream site. Copy number variation (CNV) assays were performed for three different regions of the GSTM1 gene. We demonstrated that HapMap SNP rs366631 is a non-polymorphic site. The false genotyping call arises from sequence homology, a common GSTM1 region deletion and a non-specific genotyping platform used to identify the SNP. However, the HapMap call for rs366631 genotype is an indicator of GSTM1 upstream region deletion. Furthermore, this upstream deletion can be used as a marker of GSTM1 gene deletion. Using a novel GSTM1 CNV assay, we showed a population-specific CNV in this region upstream of the gene. More than 75% of the Caucasian (CEU) samples exhibit GSTM1 deletion and none contain two copies of GSTM1. In contrast, up to 25% of African (YRI) samples were found to have two copies of GSTM1. In conclusion, HapMap rs366631 is a pseudo-SNP that can be used as a GSTM1 deletion marker. Both the pseudo-SNP allele frequency and GSTM1 upstream region CNV show population-specific patterns between CEU and YRI samples.
authors.affiliation: Section of Hematology-Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., PB Box MC2115, Chicago, IL 60637, USA.
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
authors.forename: Peixian
authors.initials: P
authors.lastname: Chen
authors.forename: Steve
authors.initials: S
authors.lastname: Wisel
authors.forename: Shiwei
authors.initials: S
authors.lastname: Duan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D044383:Black People / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics*
chemical_list: D005982:Glutathione Transferase